Role of hyperbaric oxygen therapy in patients with inflammatory bowel disease

Abstract

Purpose of review:

Hypoxia is a known contributor to inflammation in inflammatory bowel diseases (IBD), and a growing interest has emerged in pharmacologically targeting hypoxia response pathways to treat IBD. The most basic form of treatment for hypoxia is delivering higher amounts of oxygen to the intestinal mucosa. In this review we summarize the evidence in support of hyperbaric oxygen therapy (HBOT), a mechanism to deliver high amounts of oxygen to tissue, for treating IBD.

Recent findings:

Two phase 2 clinical trials in hospitalized ulcerative colitis patients suffering from moderate to severe flares has demonstrated that HBOT improves responsiveness to steroids and avoidance of rescue medical and surgical therapy. Outpatient cohort studies in perianal fistulizing Crohn’s disease and fistulizing complications of the pouch have demonstrated improved healing, particularly for complex fistulae. Several systematic reviews have now been completed and HBOT has been observed to be safe with low rates of adverse events.

Summary:

HBOT may be considered as an adjunctive treatment for hospitalized ulcerative colitis flares and Crohn’s disease related fistulae. Higher quality trials are needed to confirm efficacy.

Introduction:

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic inflammatory disorders of the gastrointestinal tract characterized by symptoms such as diarrhea, rectal bleeding, abdominal pain, and mucosal ulceration. Both CD and UC are chronic diseases with no curative options. Due to this disease’s chronicity, many complications, such as strictures, fistulas, and dysplasia, can happen over the disease’s course. Surgery and medications form the mainstay of the management. Among pharmaceuticals, biologics and small molecules that target host immune responses have effectively controlled inflammation and promoted mucosal healing.(1)

Despite recent advances in medical therapy, many patients still experience complications and do not respond to standard medical options. Although medical therapeutics have made significant strides in the last decade, there has always been a concern about the safety of these medications, especially in patients with long-term use. The quest to find non-medical options and safety concerns has led to exploring non-medical or surgical options for managing IBD. Hyperbaric oxygen therapy (HBOT) is one such option that has generated a lot of interest in the management of patients with IBD in recent years. HBOT involves breathing 100% oxygen at increased pressure to increase tissue oxygen saturation and promote healing.(2) HBOT has been used for many hypoxic and/or chronic inflammatory conditions such as gangrene, limb ischemia, chronic wounds, and chronic obstructive pulmonary disease management. In this article, we will discuss the pathogenesis, current existing evidence in regards to efficacy, and safety of the potential of HBOT as a treatment option for IBD.

Pathogenesis:

The pathogenesis of inflammatory bowel disease is a complex phenomenon that involves an intricate interplay between host genetics, host microbiome, and immune system leading to a cascade of inflammation, resulting in tissue inflammation and damage. One of the essential steps in this process is tissue hypoxia, which results from chronic inflammation and disrupts the epithelial barrier, causing microbial dysbiosis, activating neutrophils and pathogenic T cells, and leading to the overproduction of inflammatory cytokines. (3,4) This increased inflammation causes more tissue damage and long-standing complications.

HBOT is a therapeutic intervention that involves breathing 100% oxygen under increased atmospheric pressure, usually two-three times standard sea level pressure (2.0–3.0 ATA). The increased pressure and oxygen concentration in the blood plasma help deliver more oxygen to hypoxic tissues, thereby promoting tissue healing. HBOT has multiple potential pathways that can be beneficial in acute and chronic inflammation. It has been shown to reduce inflammatory cytokine production (TNFa, IFNg), increase growth factor synthesis, and promote stem cell migration from the bone marrow, thereby improving wound healing.(5)

HBOT also decreases inflammation by inhibiting neutrophil adhesion and proinflammatory cytokine (IL-1, IL-6, and TNF-a) production. It serves as an intermediary in nitric oxide and vascular endothelial growth factor signaling pathways, resulting in an improvement in hypoxia tolerance through the upregulation of response pathways (hypoxia-inducible factor (HIF) and heme-oxygenase (HO) pathways)(6–8). The cumulative effect from all these pathways is postulated to result in the improvement of tissue oxygen levels, a reduction in the inflammatory cascade, and thereby promoting tissue healing, achieving efficacious response in patients with IBD.

HBOT role in management of UC:

Role of HBOT has been studied across the IBD disease spectrum, including UC, CD and patients with ileal pouch-anal anastomosis (IPAA). (Table 1) The 1^st reported case of use of HBOT in a patient with UC was described in 1994(9). Subsequently, early case reports showed promising results in improving symptoms and reducing endoscopic and histologic scores in UC patients treated with HBOT(10–15). However, a randomized controlled trial (RCT) conducted by Pagoldh et al. in patients with severe UC flare did not show significant differences in clinical outcomes between patients treated with standard intensive UC treatment and those who received HBOT in addition to standard treatment(16). Although the study was an RCT it had significant concerns. First, they looked at longer term outcomes after discharge as opposed to immediate effects in-hospital. Second, the sample size of the study was small without apriori power calculations and it was unblinded thereby potentially resulting in differential allocation of patients to each group with more severe patients going into the HBOT group as the investigators attempted to provide the intervention for patients who needed it most. Notably, although the trial was significant, there was a numerically lower mean Mayo score in the HBOT group compared to the control group at follow-up, suggesting some efficacy may exist.

Table 1:

HBOT studies in patients with IBD

Author, Year	Study design	No. of patients	Outcomes	Adverse events
Colombel et al. 1995(37)	Case series	10 (CD)	75% response rate	Ear drum perforation
Iezzi et al. 2011(31)	Prospective study	14 (CD)	78.5% response rate	None reported
Pagoldh et al. 2013(16)	Prospective RCT	18 (UC)	No difference in outcomes	Disease worsening claustrophobia
Bekheit et al. 2016(9)	Case series	32 (UC)	32 patients showed clinical improvement	None reported
Dulai et al. 2018(17)	RCT	18 (UC)	80% achieved clinical response	Headache
Dulai et al. 2020(18)	RCT	20 (UC)	55% achieved response	None reported
Feitosa et al. 2021(30)	Prospective study	29 (CD)	78% response rate	None reported
Fahad et al. 2021(21)	Case series	21 (J-Pouch)	77% fistula response rate	None reported
Hasan et al. 2021(22)	Case series	46 (J-Pouch)	31.8 % endoscopic remission	Ear barotrauma
Lansdrop et al. 2022(29)	Prospective study	20 (CD)	60% response rate	None reported
Kante et al. 2022(33)	Prospective study	14 (CD)	64.2% clinical response	Hemotympanum Right earache

A subsequent sham-controlled study in hospitalized patients with severe UC showed promising results, with patients who received HBOT achieving clinical remission at study day 5 and 10 (50% vs. 0%, p=0.04), and being less likely to require a colectomy during hospitalization (0% vs. 38%, p=0.07).(17) Another phase 2B study looking at dosing strategies for HBOT in patients with severe UC found that a more significant reduction in disease activity was observed with 5 days of hyperbaric oxygen compared to 3 days (p=0.03) and confirmed overall efficacy rates for HBOT from the phase 2A study.(18) These results definitely show a potential for the use of HBOT in management of patients with severe UC. In future our group aims to study these results in a large multicenter RCT funded through the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK).

Patients with severe UC who fail standard medical management or develop dysplasia have a colectomy. Some patients then undergo surgery to have an IPAA or J pouch. Pouchitis is a common long-term complication in patients with UC and up to 47% of patients with J pouch can develop symptoms of pouchitis. The mainstay of management of pouchitis is antibiotics.(19) However, some patients either become dependent on chronic antibiotics (chronic antibiotic-dependent pouchitis (CADP)) or develop resistance to antibiotics (chronic antibiotic refractory pouchitis (CARP)) and stop responding. Patients with CARP or CADP do not have standardized treatment options, and biological medications form the mainstay of treatment. (20) HBOT has been studied in the management of these conditions as well. However, most of the evidence exists in the form of retrospective cohort studies. Early study results are encouraging. A retrospective case series involving 21 patients with medically refractory pouchitis and patients with fistulas were subjected to an off-label HBOT. Using standard HBOT protocols, 21 patients underwent up to 30 sessions of HBOT over 8 weeks. All patients responded to HBOT with the baseline median mPDAI (modified pouch disease activity index) score reduction from 9 (IQR 7–13) to 5 (IQR 4–10). Interestingly, of the 9 patients with active fistulae, 77.8% of patients demonstrated complete resolution of fistulae on cross-sectional imaging and endoscopic evaluation. (21) Similar results were seen in another retrospective case series involving 46 patients with CARP. All patients showed significant reductions in symptom subscores and improvements in endoscopic findings. In particular, over 50% of patients with fistulae experienced complete healing, and the concurrent use of antibiotics (p=0.019) and steroids (p= 0.021) decreased significantly.(22)

HBOT role in management of CD:

The role of hyperbaric oxygen therapy (HBOT) in managing Crohn’s disease (CD) patients has mainly focused on treating peri-anal disease such as fistulas, and extraintestinal manifestations including Pyoderma Gangrenosum (PG) and Hidradenitis suppurativa (HS). Managing peri-anal fistulas can be very challenging. Initially, case reports showed the successful use of HBOT as an adjunctive therapy in the management of peri-anal fistulas.(23–26) A case series of 10 patients treated with HBOT in conjunction with standard medical treatment showed that 80% of patients reported complete healing of the fistulas.(27)

More recently, an interventional pilot study was performed to assess the long-term effects of HBOT on fistula healing. The study included 20 patients with fistulas (<6 months in duration), all of whom underwent 40 HBOT sessions. Patients who achieved initial clinical and radiological response to HBOT were more likely to maintain response at the end of 1 year. At week 60, 20% of patients achieved fibrotic fistula with no drainage, and 60% of patients had inactive peri-anal disease activity index. (28,29) Retrospective studies in patients with perianal fistulizing Crohn’s disease, enterocutaneous fistulas, or PG who underwent HBOT showed complete healing in 82.5% of patients with fistulas and 100% healing in patients with PG.(30) In another study of 14 patients with refractory enterocutaneous fistulas, perineal disease, or PG, 11 patients had improvement, healing, and local control of inflammation after HBOT sessions.(31)

Combination therapy with infliximab, HBOT, and anti-MAP (Mycobacterium avium subspecies paratuberculosis) therapy achieved a 100% fistula healing rate that persisted for an average of 18 months with continuation of anti-MAP therapy in a case series of nine patients with resistant fistulizing Crohn’s disease. (32) A pilot study in 14 patients with stricturing Crohn’s disease of the small bowel showed that HBOT was effective and tolerable, with clinical remission rates of 50% at two months and 64.2% at six months of follow-up. (33) Overall, a systematic review of 13 studies of Crohn’s disease showed that HBOT had a clinical response rate of 78%,(34) and a meta-analysis studying various phenotypes of inflammatory bowel disease, including luminal Crohn’s disease, showed an overall clinical response rate of 86% and a clinical remission rate of 67%. (35) HBOT has shown promising results as an adjunctive therapy in managing CD patients with peri-anal fistulas and extraintestinal manifestations.

Safety of HBOT:

Hyperbaric oxygen therapy (HBOT) is generally safe and well-tolerated, but like any medical intervention, it carries a risk of adverse effects. The most common adverse effects of HBOT include otic or sinus barotrauma, confinement anxiety, hypoglycemia, seizure, shortness of breath, oxygen toxicity, and pneumothorax.(36)

Several studies have reported adverse events associated with HBOT. In one trial, nine patients experienced adverse events including perceived claustrophobia, inability to normalize middle ear pressure, and worsening clinical state, leading to premature withdrawal from the study.(16) In another randomized controlled trial, one patient experienced worsening of disease and another reported headache on the 6th treatment session, while no adverse effects were noted in a subsequent study of HBOT in patients with ulcerative colitis.(17,18) In a case series of 10 patients with severe perineal Crohn’s disease, adverse events included bilateral ear drum perforation in one patient and bad psychological intolerance in another. (37) Mild-to-moderate middle ear barotrauma was reported in 5 of the 20 patients in a study of perianal Crohn’s disease, (28) while two patients in another study reported adverse events including hemotympanum and right ear pain.(33) In a study of patients with chronic antibiotic-refractory pouchitis (CARP) and related conditions, one patient experienced persistent ear barotrauma and required myringotomy tube insertion.(22)

In a recent meta-analysis of 19 studies of HBOT in inflammatory bowel disease, 30 of 202 (14.8%) patients reported adverse events, including inner ear congestion, myopic vision changes, barotrauma, anxiety, bilateral tympanic membrane perforation, and headache.(35) While adverse events associated with HBOT are infrequent and generally not serious, caution should be exercised, and appropriate measures taken to minimize them with the use of appropriate therapeutic protocols.

Challenges of HBOT & Integration into the clinical practice:

Despite the promising results of hyperbaric oxygen therapy (HBOT) in patients with IBD, its adoption into clinical practice remains a significant challenge. One major hurdle is the lack of insurance coverage for HBOT in the United States. On average, patients require 30 HBOT sessions over a six-week period, and out-of-pocket expenses can be a significant barrier to adoption. However, in our experience, when insurance companies are made aware of the existing evidence of the benefits of HBOT, they tend to approve the procedure for patients.

In most institutions, HBOT centers are usually run by pulmonologists or physicians certified in hyperbaric medicine. Collaboration between IBD physicians and HBOT physicians is necessary to develop an HBOT program for patients with IBD. Specific scheduling slots may need to be created for patients, such as early morning or evening sessions, to accommodate the six-week treatment period.

It is important to note that currently, HBOT is not FDA-approved for patients with IBD, and patients must have a detailed discussion with their physicians regarding the potential risks and benefits before undergoing treatment. Patient buy-in is essential in this scenario.

Another challenge is positioning HBOT in the current treatment paradigm. There is still a lack of data to determine if administering HBOT early can alter the disease course and prevent long-term complications. Further research is needed to establish the optimal timing and duration of HBOT in IBD management.

Key Points:

• While biologics and small molecules targeting host immune responses have been effective in treating IBD, a substantial proportion of patients still experience complications and gaps remain in our therapeutic options.

• Mucosal hypoxia is a core driver of chronic inflammation in IBD, and HBOT may provide a novel treatment approach for this condition.

• HBOT has been observed to be safe and effective in hospitalized UC patients, and the management of Crohn’s disease related fistulae and/or complications related to ileoanal pouches.

• Further sham-controlled clinical trials are needed to confirm efficacy in routine practice cohorts.